The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are four homologous neuronal growth factors that regulate the development of the nervous system and the maintenance of the adult nervous system. GFLs promote the survival and enhance the metabolic and phenotypic status, i.e. trophic status, of several populations of neurons that are affected in neurodegenerative diseases such as Parkinson's disease. These potent survival and trophic activities of the GFLs has led to their development as therapeutic agents for the treatment of diseases and injuries of the nervous system. To this end, an understanding of the mechanisms of action of the GFLs under physiologic conditions will aid in the design of treatment regimens that utilize the GFLs. During development, GDNF has long-distance functions, such as the promotion of axon growth and target-dependent survival of motor neurons. However, whether GDNF, or other GFLs, are capable of supporting the survival and growth of neurons when only activating receptors located on their axon terminals is unclear. Furthermore, the mechanisms by which neuronal growth factors maintain the trophic status of neurons are not well established. Nerve growth factor (NGF), a member of the neurotrophin family of growth factors, regulates the trophic status of sympathetic neurons via activation of Ret, the heterologous receptor tyrosine kinase for the GFLs. Remarkably, NGF does not activate Ret through the production of GFLs, and instead NGF acts via a cross-talk mechanism between TrkA, the NGF receptor, and Ret. My laboratory has the rare ability to conduct biochemical and cell biological experiments on isolated axons and cell bodies of primary neurons using compartmentalized cultures, bringing these important questions within our grasp. As part of our long-term goal of delineating the mechanisms of action of neurotrophic factors in the developing and adult nervous system we propose the following: 1) to test the hypothesis that GDNF acts as a long-distance survival and growth-promoting factor, 2) to test the hypothesis that the down regulation of the GDNF receptor, Ret, upon activation dictates the local and long-distance signaling capabilities of GDNF, 3) to test the hypothesis that NGF augments Ret activation via the inhibition of the activity-dependent degradation of Ret through the modulation of Cbl-3 and CD2AP, two important regulators of receptor tyrosine kinases. The GDNF family ligands (GFLs) are currently being investigated for the treatment of neurodegenerative diseases such as Parkinson's disease, Huntington's disease, ALS, and retinal diseases, and for injuries of the nervous system such as spinal cord injury (SCI) and stroke. Neurturin, a member of this family, is currently in phase II clinical trials for Parkinson's disease. Therefore, an understanding of the local and long-distance signaling capacities of the GFLs and an understanding of the molecular mechanisms by which GFLs convey survival and growth will aid in the design of treatment strategies that employ GFLs.